Aim and Objective: Plasmodium knowlesi has been recently recognized as a human malarial parasite, particularly in the region of south-east Asia. Unlike human host, P. knowlesi cannot salvage pyrimidine bases and relies solely on nucleotides synthesized from de novo pyrimidine pathway. The enzymes involved in this are also unique in terms of their structure and function to its human counterpart. Thus, targeting Dihydroorotase, an enzyme involved in the pyrimidine biosynthesis, provides a promising route for novel drug development.
Materials and Methods: The 3D structure of P. knowlesi Dihydroorotase was predicted, refined and validated. Multiple docking was performed and the resultant complex was used for 3D structurebased pharmacophore modelling. A combinatorial library of 2,664,779 molecules was generated and used for structure based virtual screening. The stability of resultant compounds was checked using simulation studies.
Results: The modelled 3D structure of P. knowlesi Dihydroorotase enzyme is relaxed by running an MD simulation of 20 ns, and structure is validated by using Ramachandran plot and G-factor analysis. A five point based pharmacophore model was created and used as a query for screening in house database. The stability of two negatively charged compounds was studied, and ZINC22066495-DHOase complex was more stable throughout the simulation.
Conclusion: The present study shows that ZINC22066495 compound has a high potential for disrupting P. knowlesi DHOase enzyme and may be used as a potential lead molecule for effective pyrimidine biosynthesis inhibition in P. knowlesi.
Keywords: Docking, structure based virtual screening, molecular dynamics simulation, drug design, pharmacophore.